The Role of Striatal Astrocytic Dopamine D2 Receptor Signaling in the Pathogenesis of LRRK2-Mediated Parkinson's Disease

Mutations on the LRRK2 gene, which increase the encoded protein's kinase activity, are common genetic causes of familial Parkinson's disease (PD). Noncoding variants at the LRRK2 locus have also been linked to an increased risk of sporadic PD. Thus, LRRK2 is a promising therapeutic target in familial and sporadic PD. While small molecule LRRK2 kinase inhibitors are currently tested in clinical trials, the precise pathological mechanisms of LRRK2 mutations remain unknown. Several studies have supported the idea of non-cell autonomous mechanisms leading to DA neuron death, a pathological PD hallmark. We observed elevated astrogliosis in the caudate/putamen of postmortem LRRK2G2019S carriers and LRRK2G2019S knockin mice. Together with a well-accepted role of LRRK2 in synapse and inflammation, this suggests that aberrant LRRK2 kinase activity increases the inflammatory burden in the nigrostriatal synapse by involving astrocytic activation. A limited understanding of the astrocyte signaling pathways relevant to PD hampered progress in establishing astrocyte dysfunction with PD pathophysiology. As our findings show a role of LRRK2 in the dopamine D2 receptor (D2R) signaling in the striatal astrocytes, the overarching goal of this study is to link astrocytic LRRK2- mediated D2R signaling impairments to neuroinflammation in these mice representing prodromal PD. Overall, we aim to explore if LRRK2-mediated striatal astrocyte D2R signaling perturbations exacerbate early synaptic inflammatory processes that lead to PD. We will utilize innovative genetic models and viral approaches to manipulate D2R signaling in identified astrocytes, allowing us to dissect D2R signaling-mediated mechanisms with high specificity in a specific cell type manner. Aim 1 will mechanistically link impaired D2R signaling and inflammation in striatal LRRK2G2019S astrocytes. In Aim 2, we will manipulate D2R signaling specific in striatal astrocytes and assess how this influences inflammation, neurotoxicity, and behavior in vivo. In light of the clinical testing of small molecule inhibitors against LRRK2 kinase and D2R agonists in the clinical setting, our work is crucially placed to set the framework for developing disease-modifying strategies targeting astrocyte dopamine signaling in the striatum.